Quadruple Stimuli-Responsive Mechanized Silica Nanoparticles: A Promising Multifunctional Nanomaterial for Diverse Applications

Article abstract of DOI:10.1002/chem.201704245

Novel quadruple stimuli-responsive mechanized silica nanoparticles were constructed by installation of supramolecular nanovalves onto the exterior surface of mesoporous silica nanoparticles. The release of cargo molecules is triggered by acid/Zn²⁺/alkali/reduction potential stimuli. This has potential application in the development of drug delivery systems or construction of smart anticorrosion coatings.

Full text of DOI:10.1002/chem.201704245

A Journal of
Accepted Article
Title: Quadruple Stimuli-Responsive Mechanized Silica Nanoparticles:
A Promising Multifunctional Nanomaterial for Diverse Applications
Authors: Chendi Ding, Ling Tong, and JiaJun Fu
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To be cited as: Chem. Eur. J. 10.1002/chem.201704245
Link to VoR: http://dx.doi.org/10.1002/chem.201704245
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Quadruple Stimuli-Responsive Mechanized Silica Nanoparticles:
A Promising Multifunctional Nanomaterial for Diverse
Applications
ChenDi Ding,[a] Ling Tong[a] and JiaJun Fu*[a]
Abstract: Novel quadruple stimuli-responsive mechanized silica
nanoparticles were constructed by installation of supramolecular
nanovalves onto exterior surface of mesoporous silica nanoparticles.
The
release
of
cargo
molecules
is
triggered
by
acid/Zn2+/alkali/reduction potential stimuli, which offers application
prospects of developing the drug delivery systems or construction of
smart anticorrosion coatings.
Stimuli-responsive controlled release systems, which are
capable of executing predefined missions of on-demand cargo
release through chemical or physical changes in configurations
upon external stimuli, have received considerable attentions.1
Inorganic or polymeric materials, acting as nanocarriers, are
decorated by various gatekeepers, including nanoparticles,
polymer, proteins, DNA, and supramolecular architectures,
which provide the ideal templates for synthesizing stimuli-
responsive controlled release systems.2 Recently, with the
development and deepening of research for supramolecular
host-guest
chemistry,
the
elaborately
designed
rotaxanes/pseudorotaxanes as supramolecular nanovalves have
been immobilized on the exterior surface of mesoporous silica
nanoparticles (MSNs) and regulated the diffusion in or out of the
cargo molecules, which is depending on the stimuli-induced
mechanical movement of macrocyclic molecules along synthetic
linear molecular stalks.3 Based on these assembly conception, a
vast of mechanized silica nanoparticles (MSNPs) have emerged
in the last decade and showed the great potential in the field of
drug delivery systems due to the inherent ability of making the
timely feedback to endogenous stimuli surrounding tumor issues
(pH,4 redox,5 enzyme6 etc.) or exogenous stimuli (light,7 thermo8
etc.) and delivering anticancer drugs to targeted tumor sites.
Compared with single or dual stimuli-responsive systems,
multiple stimuli-responsive MSNPs not only provide the
possibility of precisely controlling the dosage and location for
cargo molecules via rational arrangement of the multi-stimuli,9
but also achieve more functions, which will undoubtedly expand
their potential application fields by integrating appropriate stimuli
into one controlled release system. Also, the more kinds of
stimulus that controlled release systems could recognize, the
smarter it would be for multiple application fields.Therefore,
recently more and more researchers place an emphasis in
Scheme 1. Schematic illustration of (A) fabrication of QSR-MSNPs; (B)
stimuli-responsive release mechanism of QSR-MSNPs.
developing multiple stimuli-responsive MSNPs.
Herein, we tailored the acid/Zn2+/alkali/reduction potential
quadruple-stimuli responsive MSNPs (QSR-MSNPs) for the first
time to achieve multiple application purpose, where the MSNs
were employed to accommodate cargo molecules and the
crucial components were [2]pseudorotaxanes, composed of
water soluble pillar[5]arene (WP[5], see Supporting Information
for details, Figure S1 and S2) and 2,2’-dithiobis(ethanamine)-N-
butoxybenzene (Cys-BOP, see Supporting Information for
details, Figure S3-S10). In neutral solution, WP[5] bind with the
first recognizable motif, cystamine (Cys) in linear functional
stalks, preventing the undesirable leakage of cargo molecules.
The working mechanism of QSR-MSNPs is schematically
depicted in Scheme 1B. The four different controlled release
approaches are explained as following: (i) alkali stimulus drives
WP[5] to transfer from Cys motif to the second recognizable
motif, N-butoxybenzene (BOP), leaving entrances for cargo
molecules; (ii) acidic stimulus facilitates the precipitation of WP[5]
from QSR-MSNPs and the gatekeepers are lost. (iii) the addition
of Zn2+ generates the competitive binding interactions, which
spurs Zn2+-WP[5] complexes to dissociate from the linear
[a]
Dr. C. Ding, L. Tong, Prof. J. Fu
School of Chemical Engineering
Nanjing University of Science and Technology
Nanjing 210094 (P.R. China)
E-mail: fujiajun668@gmail.com
Supporting information for this article is given via a link at the end of
the document.
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on the surface exterior (Figure S14). After loading rhodamine
(RhB, Figure S13(c)) and undergoing the self-assembly process
between WP[5] and Cys-BOP, QSR-MSNPs were successfully
constructed. The FTIR spectrum of QSR-MSNPs exhibits the
characteristic peak of C=O stretching vibration at 1600 cm-1 and
C-O asymmetrical stretching vibration at 1175 cm-1, proving the
incorporation of WP[5] and RhB. In addition, as the assembly
process proceeded step-by-step, XRD peak intensities gradually
decreased and the texture parameters dramatically declined
concurrently (Figure S15, S16 and Table S1) due to the partial
occupation of pore volume by functional stalks and RhB. The
TEM image for QSR-MSNPs illustrates the uniform coverage of
supramolecular nanovalves on surface of MSNs (Figure. 1B).
According to the results from thermogravimetric analysis (TGA),
the contents of grafted CMTES and CysBOP were determined
as 0.86 mmol g-1 and 0.43 mmol g-1, respectively, as well as the
weight loss of RhB and WP[5] was roughly estimated as 13.1%
(Figure S17).
Figure 1. TEM image of (A) MSNs; (B) QSR-MSNPs; (C) FTIR spectra of
MSNs, (b) QSR-MSNPs; (D) 13C SS-NMR spectra of (a) MSNs, (b) MSNs-Cl,
(c) MSNs-Cys-BOP.
Release experiments were carried out under different types of
stimuli in PBS (pH 7.4). The loading of RhB was calculated to be
173.3 μmol g-1 QSR-MSNPs (Figure S18). Prior to application of
triggers, the flat baseline within 24 h shown in Figure. 2A
demonstrated the negligible leakage of RhB, meaning the closed
pore orifices. The complexation between WP[5] and Cys-BOP
functional stalks; (vi) after exerting reduction potential, the
disulfide bonds in Cys motif are broken, resulting in the
disintegration of supramolecular nanovalves.
The typical MCM-41 type, mono-dispersed MSNs with the
average diameter of about 105 nm are shown in the
transmission electron microscopy (TEM) image (Figure. 1A). The
high-ordered hexagonal mesoporous structure was confirmed by
TEM image and small-angle X-ray diffraction (SA-XRD) data
(Figure S11). N2 absorption-desorption isotherm of MSN
exhibited a type IV isotherm with a high specific surface area of
1135.4 m2 g-1, a large total pore volume of 0.89 cm3 g-1, and the
narrow pore diameter of 2.38 nm (Figure S12). The synthetic
route for QSR-MSNPs is illustrated in Scheme 1A. The surface
1
was investigated by H NMR spectroscopy. The addition of 1.0
equiv. of WP[5] to a solution of Cys-BOP in D2O resulted in the
remarkable upfield chemical shifts of the Cys protons, Hh (Δδh=-
1.1 ppm), Hi (Δδi=-3.1 ppm), Hj (Δδj=-2.8 ppm), and Hk (Δδk=-1.0
ppm) due to the shielding effect of the electron-rich cavities of
WP[5], while no obvious change was observed for the BOP
protons (Figure. 2C (d and e)). Further isothermal titration
calorimetry (ITC) measurement indicated that WP[5] could form
a stable 1:1 binding stoichiometry with an association constant
of 1.21×106 M-1 (Figure S19). Under neutral solution, WP[5]
resided on the Cys motif steadily, near the pore orifices.
[2]pseudorotaxane 1a sealed the entrances for diffusion out of
RhB. Upon addition of HCl, the substantial RhB was released,
and the cumulative release efficiency was 9.09 % at pH=6.0 and
increased to 69.95% at pH=2.0 after 24 h. As shown in Figure.
2C (f). Adding DCl into WP[5]⊃CysBOP caused the
disappearance of protons of WP[5] and the slight shifting of
partial Cys-BOP protons was ascribed to the protonation of -NH-
and -NH2 groups. Based on these results, it is understandable
that the protonation of carboxylate groups on both ends of WP[5]
leads to the precipitation of WP[5] (Figure S20), which equates
to open the supramolecular nanovalves and frees RhB. The
phenomenon of alkali-stimuli responsive release was also
observed (Figure. 2B). With the addition of NaOD, the Cys
protons returned back to their original locations, whereas the
protons in BOP motif strongly shielded (Δδc,d,g,e,f=-0.2, -1.7, -1.6,
-1.0, and -1.1 ppm, Figure. 2C (a and b)). Obviously, alkali
stimulus drives WP[5] mechanically move from Cys motif to BOP
motif. The ITC data also substantiate this migration process. The
association constant between WP[5] and Cys motif is controlled
by pH of solution, which decreased from 4.96×105 M-1 (neutral)
to 1.62×104 M-1 (alkali) (Figure S21). In contrast, the association
of
MSNs
was
successively
functionalized
with
chloromethyltriethoxysilane (CMTES) and Cys-BOP to afford
MSNs-Cl and MSNs-Cys-BOP, respectively. The whole
functionalization process was characterized by fourier transform
infrared spectroscopy (FTIR) and 13C solid-state nuclear
magnetic resonance (13C SS-NMR). As shown in Figure.1D (b),
the resonance signal at 22.9 ppm was assigned to methylene
group of MSNs-Cl; and the typical absorption peaks of C-H
asymmetrical stretching vibration (2856 and 2958 cm-1) and C-Cl
stretching vibration (690 cm-1) in the FTIR spectrum (Figure
S13(a)) also suggested that CMTES anchored on the surface of
MSNs. For MSNs-Cys-BOP, FTIR result showed new absorption
bands at 1546, 1513 and 1383 cm-1, which are respectively
assigned to the characteristic absorption peak of shear vibration
of N-H, skeleton vibration of benzene ring and C-N stretching
vibration, indicating the covalent conjugation of Cys-BOP (Figure
S13(b)). Furthermore, the 13C SS-NMR spectrum of MSNs-Cys-
BOP (Figure.1D (c)) displays two series of signals: (i) Ca’, Cg,
and Ch (29.2-33.8 ppm), Cc and Cd (35-37.3 ppm), Cb, Ce and Cf
(46.4-54.2 ppm) are all belonging to the aliphatic moieties; (ii) Ci
(67.9 ppm), Ck, Cl and Cm (125.6-131.2 ppm), and Cj (165.3 ppm)
are corresponding to the phenol moieties. The uniform
distributions of C, N and S within the MSNs-CysBOP, exhibited
in energy dispersive X-ray analysis (EDAX) mapping images,
also suggest the full coverage of the intact functionalized stalks
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Figure 3. (A) Zn2+-triggered release profiles of RhB; (B) Reductive/oxidative
potential-triggered release profiles of RhB; (C) FTIR spectrum of QSR-MSNPs
treated with -1.0 V potential. (Insert: expanded spectrum) (D) 13C SS-NMR
spectrum of QSR-MSNPs treated with -1.0 V potential.
SHE), the release trend of RhB was greatly inhibited. This is due
to that the disulfide could be re-formed under oxidative
environment13 and therefore the blocking effect of
supramolecular switches was partially recovered. The potential
sensitivity is associated with the disulfide bonds in Cys motif,
which is evidenced by the FTIR and 13C SS-NMR spectra
(Figure 3C and 3D) of residue solids collected after receiving
reduction potential stimulus: The absorption peak at 1380 cm-1
represents the C-N stretching vibration, at the same time, a
weak absorption peak appeared at 2545 cm-1, which confirms
the existence of thiol groups. Combined with results of 13C SS-
NMR, the organic components immobilized on surface of MSNs
is inferred as methylcysteamine, testifying that the generating
electrons entered into cavity of WP[5] and subsequently cleave
the disulfide bonds, completely undermining the supramolecular
nanovalves. It is worth noting that glutathione (GSH) did not
initiate the release of RhB from QSR-MSNPs (Figure S29).
Calculation results indicated that due to the size effect, GSH
cannot entered into the cavity of WP[5], originally complexed
with Cys, and have no opportunity to contact with disulfide
bonds (Figure S30).
Taking advantage of slightly acidic environments in cancerous
tissues, endosomes and lysosomes as compared to
physiological pH in the blood and normal tissues, QSR-MSNPs
have the potential to deliver anticancer drugs to the tumor sites.
In order to evaluate QSR-MSNPs as qualified nanovehicles,
MTT assay was conducted against MCF-7 cancer cells and
NIH3T3 normal cells in the presence of various concentrations
of empty QSR-MSNPs, doxorubicin (DOX)-loaded QSR-MSNPs
and free DOX. As model anticancer drug for substitution of RhB,
DOX was loaded into QSR-MSNPs, (the encapsulation
efficiency is 121.4 μmol g-1, Figure S31) which also exhibited the
acid stimulus-responsive release characteristic, while under
neutral condition, even with the addition of 10% serum, DOX
barely released (Figure. 4A). As shown in Figure. 4B and Figure.
S32, after incubation for 24 h, empty QSR-MSNPs were
nontoxic to MCF-7 and NIH3T3 normal cells at all the tested
concentration, revealing their excellent biocompatibility. In
Figure 2. (A) Acid-triggered release profiles of RhB; (B) alkali-triggered
release profiles of RhB, insert image: TEM image of QSR-MSNPs after the
release experiment in alkaline environment; (C) 1H NMR spectra (300 MHz,
D2O, 298K): (a) 5mM Cys-BOP, pD=10.0; (b) 5mM Cys-BOP and 5mM WP[5],
pD=10.0; (c) 5 mM WP[5]; (d) 5 mM Cys-BOP and 5 mM WP[5], pD = 7.0; (e)
5 mM Cys-BOP, pD = 7.0; (f) 5 mM Cys-BOP and 5 mM WP[5], pD = 2.0.
constant between WP[5] and BOP motif (see Supporting
Information for synthetic procedure, Figure S22-S25) was stable
and calculated as 1.39×105 M-1 (Figure S21). For QSR-MSNPs,
WP[5] encircled on the BOP motif, signifying that the
gatekeepers are far away from the pore orifices.
[2]pseudorotaxane 1b works as opened switch, realizing the
release of RhB from the mesopores. Noticeably, TEM photo
(Figure S26) shows that the morphology of QSR-MSNPs after
release experiment remained stable, which excludes the
possibility that such release behavior is caused by disassembly
of scaffold material in alkaline environment. The control
experiments were also conducted to certify the blocking role of
WP[5] (Figure S27).
There have been some reports concerning that divalent metal
ions has the ability to damage the structures of WP[6]-based
supramolecular assemblies.10,11 In this study, in the presence of
Zn2+, QSR-MSNPs showed excellent performance of controlled
release. The release efficiency of RhB from QSR-MSNPs was
observed to increase with the increase of Zn2+ concentration.
After completing release experiment, the Zn2+-WP[5] complexes
were detected in the supernatant (Figure S28), which
demonstrates the chelation of Zn2+ between carboxylate groups
on WP[5] destroy the WP[5]⊃CysBOP, making WP[5] dissociate
from the functional stalks and accomplishing the release task.
The natural discrepancy in Zinc concentration between normal
issues and central nervous system disease sites12 inspires us to
develop Zn2+-triggered controlled release systems, and thus
achieve active targeted drug delivery. Astoundingly, when
reduction potential (-1.0 V vs SHE) was exerted, RhB was
rapidly released and by exerting oxidative potential (+1.0 vs
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Figure 4. (A) Acid-triggered release profiles of DOX from QSR-MSNPs; (B)
Cytotoxicity of empty QSR-MSNPs, DOX-loaded QSR-MSNPs, and free DOX
after 24 h of cell culture using MCF-7 cells; (C) Fluorescent images of MCF-7
cells incubated with QSR-MSNPs (12.5 μg mL-1) for different incubation time,
from left to right: Hoechst 33342 (blue), DOX (red) and a merged images.
Figure 5. (A) SVET results of (A) the control coating sample, (B) QSR-MSNPs
loaded coating sample for immersion in 0.5 M NaCl of (a) 5 h, (b) 12 h, (c) 24
h. (C) Schematic illustration of (a) corrosion of AA2024; (b) working
mechanism of QSR-MSNPs in smart anticorrosion coatings.
contrast, significant growth inhibition on MCF-7 cancer cells was
observed when incubated either with DOX-loaded QSR-MSNPs
or free DOX (Figure S33). The cytotoxicity presented clear
dosage-dependency (the IC50 was calculated to be which is
126.3 μg/mL and the corresponding DOX amount is 8.3 μg/mL)
and the cell viability remarkably decreased as the increase of
the effective DOX concentration. For comparison, DOX-loaded
QSR-MSNPs manifested the slightly lower inhibition activity than
those treated with the free DOX at the equivalent dosage. The
representative fluorescence merged images shown in Figure. 4C
depicts the three stages for transport process of DOX: (i) DOX
was confined within QSR-MSNPs and almost no DOX red
fluorescence was observed due to the quenching effects. (ii)
QSR-MSNPs were taken up by cancer cells and acid-triggered
intracellular release of DOX occurred. Noticeably, DOX was
primarily located in the cell cytoplasm at this stage. (iii) DOX
eventually diffused into nuclei and showed the killing effect
toward MCF-7 cells.
Another potential application of QSR-MSNPs is to construct
smart anticorrosion coatings for protection of aluminum alloys,
which often suffers from local corrosion due to its poor corrosion
resistance. Once the aggressive species (Cl-, O2 etc.) penetrate
through protective coatings and reach aluminum alloy surface,
the local corrosion will be initiated, which leads to the
environmental changes in the local regions: (i) in the corrosive
micro-anodic regions, the dissolution of metallic Al and
hydrolysis of Al3+ causes local acidification; (ii) in the corrosive
micro-cathodic regions, the oxygen reduction reaction results in
the local alkalization14; (iii) electrons transferring from anodic to
cathodic regions bring about the decrease in surface
electrochemical potential15 (for AA2024, -1.05 V vs. SHE).
QSR-MSNPs possessing acid/alkali/reduction potential stimuli-
responsiveness guarantees that no matter where QSR-MSNPs
are located (micro-anodic, cathodic regions or regions between
them), they can rapidly respond to these three stimuli and
immediately give the feedback to release corrosion inhibitors to
restrict corrosion propagation. To testify the above concept,
benzotriazole (BTA) was employed as corrosion inhibitor and
loaded into QSR-MSNPs (loading amount: 142.7 µmol g-1,
Figure S34). As shown in Figure S35, the release of BTA
triggered by acid/alkali/reduction potential stimuli was also
observed. QSR-MSNPs as nanocontainers were doped into sol-
gel coating (Figure S36) and the self-healing performances of
hybrid coating was evaluated by scanning vibrating electrode
technique (SVET). As shown in Figure 5, the corrosion current
density of hybrid coating around artificial defects decreased
rapidly over time, while for the control coating (so-gel coating
without QSR-MSNPs), the current density kept growing to 37.95
µA cm-2 at the end of monitoring. SEM images and EDAX
mapping (Figure S37) for artificial defects verify the role of QSR-
MSNPs in the self-healing process. The timely release of BTA
and subsequent formation of BTA molecular film on local
damaged region account for the effect suppression of local
corrosive activity. (Figure 5C).
In summary, the quadruple stimuli-responsive mechanized silica
nanoparticles were successfully prepared, in which the
supramolecular nanovalves installed onto the exterior surface of
MSNs implement the switch behaviors and control the release of
cargoes. The unique controlled release properties expand their
application fields. QSR-MSNPs are expected to be used in the
field of targeted drug delivery systems to avoid side effects due
to
their
acid/Zn2+
stimuli-responsiveness.
Meanwhile,
acid/alkali/reduction potential stimuli-responsive controlled
release characteristic enhances the response sensitivity of QSR-
MSNPs as nanocontainers in smart anticorrosion coatings, and
thus improves self-healing effects.
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12472; c) T. Chen, N. Yang, J. Fu, Chem. Commun. 2013, 49, 6555-
6557; d) Z. Li, D. L. Clemens, B. Y. Lee, B. J. Dillon, M. A. Horwitz, J. I.
Zink, ACS nano 2015, 9, 10778-10789.
Acknowledgements
This research was financially supported by the National Nature
Science Foundation of China (No. 51672133), the Natural
Science Foundation of Jiangsu Province (No. BK20161496), the
fundamental Research Funds for the Central Universities (No.
30915012207), Postgraduate Research & Practice Innovation
Program of Jiangsu Province (No. KYCX17_0374) and a project
funded by the Priority Academic Program Development of
Jiangsu Higher Education Institutions (PAPD). Authors ChenDi
Ding and Ling Tong contributed equally to this work.
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10.1002/chem.201704245
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
ChenDi Ding, Ling Tong, JiaJun Fu*
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Quadruple Stimuli-Responsive
Mechanized Silica Nanoparticles: A
Promising Multifunctional
Nanomaterial for Diverse
Applications
Mesoporous silica nanoparticles grafted with unique supramolecular nanovalves:
The controlled release behaviors could be triggered by quadruple stimuli-
acid/alkaline/Zn2+/reduction stimuli.
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